Method for preparing intermediate of 4-methoxypyrrole derivative

ABSTRACT

The present invention relates to a method for preparing intermediates of 4-methoxypyrrole derivatives. The preparation method according to the present invention has advantages that the production cost can be lowered by using inexpensive starting materials, a high-temperature reaction is not required as a whole, inexpensive and non-explosive reagents are used instead of (trimethylsilyl)diazomethane, and further an intermediate of 4-methoxypyrrole derivatives can be prepared as a whole at a high yield.

TECHNICAL FIELD

The present invention relates to a method for preparing intermediatesused in the preparation of 4-methoxypyrrole derivatives.

BACKGROUND OF ART

Gastrointestinal track ulcers, gastritis, and reflux esophagitis occurwhile the balance between aggressive factors (e.g., gastric acid,Helicobacter pylori pepsin, stress, alcohol and tobacco) and protectivefactors (e.g., gastric mucosa, bicarbonate, prostaglandins, the degreeof blood supply, etc.) is destroyed. Therefore, a therapeutic agent forgastrointestinal damage such as gastrointestinal track ulcer, gastritisand reflux esophagitis is divided into a drug for inhibiting theaggressive factors and a drug for enhancing the protective factors.

Meanwhile, it is reported that gastrointestinal track ulcers, gastritisand reflux esophagitis occur ulcers even without an increase insecretion of gastric acid. Thus, as much as the aggressive factorincreases, a reduction in protective factors due to a pathologicalchange of the gastric mucosa is thought to play an important role in theoccurrence of gastric ulcers. Therefore, in addition to drugs forinhibiting the aggressive factor, drugs for enhancing the protectivefactors are used for the treatment of gastrointestinal ulcer andgastritis. As the drugs for enhancing protective factors, mucosalprotective drugs which are attached to the ulcer site to form aphysicochemical membrane, drugs that promote the synthesis and secretionof mucus have been known.

On the other hand, Helicobacter pylori (H. pylori), which is a bacteriapresent in the stomach, has been known to cause chronic gastritis,gastric ulcer, duodenal ulcer and the like, and a number of patientswith gastrointestinal damages are infected with H. pylori. Therefore,these patients should take antibiotics such as clarithromycin,amoxicillin, metronidazole and tetracycline, together with anti-ulceragents such as a proton pump inhibitor, or a gastric pump antagonist.Consequently, various side effects have been reported.

Therefore, there is a need to develop anti-ulcer drugs which inhibit thesecretion of gastric acid (e.g., proton pump inhibitory activity) andenhance protective factors (e.g., an increase in mucus secretion) and atthe same time have disinfectant activity against H pylori.

In this connection, Korean Patent No. 10-1613245 discloses that a4-methoxypyrrole derivative or a pharmaceutically acceptable saltthereof has excellent anti-ulcer activity (i.e., proton pump inhibitoryactivity, etc.) and disinfectant activity against H. pylori, and thuscan be effectively used for the prevention and treatment ofgastrointestinal damage due to gastrointestinal track ulcer, gastritis,reflux esophagitis or Helicobacter pylori.

In the preparation of the 4-methoxypyrrole derivative described in theabove patent, the following compound is prepared as an intermediate.

According to the description of the above patent, the intermediate isprepared from 2,4-difluorophenylglycine, and the preparation methodconsists of four steps in total (Steps (8-1) to (8-3) of Example 8described in Korean Patent No. 10-1613245). However, according to thepreparation method of the above patent, the total yield is as low as9.0%, a high-temperature reaction is required as a whole, and thusexpensive equipment is required. Especially,(trimethylsilyl)diazomethane is used as a reactant, but this reagent isnot only expensive but also explosive and thus is not suitable forindustrial mass production.

Given the above circumstances, the present inventors have conductedintensive studies on a new preparation method capable of preparing theabove intermediate. As a result, the inventors have found a preparationmethod in which a high-temperature reaction is not required as a wholeas in the preparation method described later, and inexpensive,non-explosive reagent is used instead of (trimethylsilyl)diazomethane,and further, the yield is improved as a whole, thereby completing thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION Technical Problem

It is an object of the present invention to provide a method forpreparing an intermediate which can be usefully used in the preparationof 4-methoxypyrrole derivatives.

Technical Solution

In order to achieve the above object, the present invention provides apreparation method as shown in the following Reaction Scheme 1, and morespecifically, the preparation method comprises the steps of:

1) reacting a compound represented by the following Chemical Formula 1-1with ammonium chloride, sodium cyanide, or potassium cyanide, followedby reaction with an acid to prepare a compound represented by thefollowing Chemical Formula 1-2;

2) protecting a compound represented by the following Chemical Formula1-2 with an amine protecting group (P) to prepare a compound representedby the following Chemical Formula 1-3;

3) reacting a compound represented by the following Chemical Formula 1-3with (i) methylpotassium malonate or methylsodium malonate, (ii)carbonyldiimidazole, and (iii) magnesium halide, followed by reactionwith an acid to prepare a compound represented by the following ChemicalFormula 1-4;

4) reacting a compound represented by the following Chemical Formula 1-4with N,N-dimethylformamide dimethylacetal to prepare a compoundrepresented by the following Chemical Formula 1-5;

5) reacting a compound represented by the following Chemical Formula 1-5with dimethyl sulfate to prepare a compound represented by the followingChemical Formula 1-6; and 6) reacting a compound represented by thefollowing Chemical Formula 1-6 with an acid via deprotection to preparea compound represented by the following Chemical Formula 1.

Hereinafter, the present invention will be described in detail for eachstep.

(Step 1)

The step 1 relates to Strecker amino acid synthesis, which is a step ofpreparing an amino acid like a compound represented by the ChemicalFormula 1-2 from the Chemical Formula 1-1.

The reaction consists substantially of two reactions. First, the firstreaction is to react a compound represented by the Chemical Formula 1-1with ammonium chloride, and sodium cyanide, or potassium cyanide.

Preferably, the molar ratio of the compound represented by the ChemicalFormula 1-1 to ammonium chloride is 10:1 to 1:10, more preferably 5:1 to1:5, and most preferably 3:1 to 1:3. Preferably, the molar ratio of thecompound represented by the Chemical Formula 1-1 to sodium cyanide orpotassium cyanide is 10:1 to 1:10, more preferably 5:1 to 1:5, and mostpreferably 3:1 to 1:3.

Preferably, as a solvent for the first reaction, an alcohol having from1 to 4 carbon atoms, and ammonium hydroxide or ammonium carbonate areused. More preferably, the alcohol having 1 to 4 carbon atoms ismethanol, ethanol, propanol, iso-propanol, butanol, or tert-butanol.

Preferably, the first reaction is carried out at 0° C. to 40° C. Whenthe reaction temperature is less than 0° C., there is a problem that theproduction yield is lowered. When the reaction temperature exceeds 40°C., the production yield does not substantially increase.

Preferably, the first reaction is carried out for 1 to 48 hours. Whenthe reaction time is less than 1 hour, there is a problem that thereaction does not proceed sufficiently and thus the production yield islowered. When the reaction time exceeds 48 hours, the production yielddoes not substantially increase.

On the other hand, after the first reaction is completed, a step ofpurifying the product may be included, if necessary. Preferably, thepurification is carried out by crystallizing a cyanamide compound fromthe product of the reaction. As the crystallization solvent, water andan alcohol having 1 to 4 carbon atoms can be used. Preferably, thealcohol having 1 to 4 carbon atoms is methanol, ethanol, propanol,iso-propanol, butanol, or tert-butanol. Preferably, water is added tothe reaction product and cooled to 10 to 15° C. Then, an alcohol having1 to 4 carbon atoms is added thereto and stirred for 10 minutes to 2hours.

After the first reaction is completed, a second reaction is carried outin which the product of the first reaction is reacted with an acid.

As the acid that can be used, acetic acid or hydrochloric acid can bementioned. Preferably, acetic acid and hydrochloric acid are usedtogether. The acid not only acts as a reactant in the second reaction,but also acts as a solvent. Therefore, it is preferable to use the acidin an amount sufficient to dissolve the first product.

Preferably, the second reaction is carried out at 80 to 120° C. When thereaction temperature is less than 80° C., there is a problem that theproduction yield is lowered. When the reaction temperature exceeds 120°C., the production yield does not substantially increase.

Preferably, the second reaction is carried out for 1 to 10 hours. Whenthe reaction time is less than 1 hour, there is a problem that thereaction does not proceed sufficiently and thus the production yield islowered. When the reaction time exceeds 10 hours, the production yielddoes not substantially increase.

On the other hand, after the second reaction is completed, a step ofpurifying the product may be included, if necessary.

(Step 2)

The step 2 is a step of protecting a compound represented by theChemical Formula 1-2 with an amine protecting group (P), which is a stepof preparing a compound represented by the Chemical Formula 1-3 byreacting a compound represented by the Chemical Formula 1-2 with acompound capable of introducing an amine protecting group (P).

Preferably, the amine protecting group (P) is tert-butoxycarbonyl (Boc),fluorenylmethyloxycarbonyl (Fmoc), Tosyl, or Acyl. In addition, thecompound capable of introducing an amine protecting group (P) refers tovarious compounds used in the art for introducing the protecting group.For example, when the amine protecting group (P) is atert-butoxycarbonyl (Boc), the compound capable of introducing the amineprotecting group includes di-tert-butyl dicarbonate.

Preferably, the molar ratio of the compound represented by the ChemicalFormula 1-2 to the compound capable of introducing the amine protectinggroup (P) is 10:1 to 1:10, and more preferably 3:1 to 1:5.

Preferably, the reaction is carried out in the presence of a base. Asthe base, triethylamine, diisopropylamine, diisopropylethylamine,potassium carbonate, potassium hydrogencarbonate, sodium carbonate,sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithiumhydroxide, sodium methylate, potassium butyrate, or cesium carbonate canbe used, and preferably, sodium hydrogencarbonate is used. Preferably,the molar ratio of the compound represented by the Chemical Formula 1-2to the base is 1:1 to 1:10, and more preferably 1:1 to 1:5.

Preferably, as a solvent for the above reaction, water, tetrahydrofuran,dioxane, methylene chloride, butyl alcohol, tetrahydrofuran, or amixture thereof may be used. Preferably, water and tetrahydrofuran areused together.

Preferably, the reaction is carried out at 10 to 40° C. When thereaction temperature is less than 10° C., there is a problem that theproduction yield is lowered. When the reaction temperature exceeds 40°C., the production yield does not substantially increase. Morepreferably, the reaction is carried out at 20 to 30° C.

Preferably, the above reaction is carried out for 1 to 48 hours. Whenthe reaction time is less than 1 hour, there is a problem that thereaction does not proceed sufficiently and thus the production yield islowered. When the reaction time exceeds 48 hours, the production yielddoes not substantially increase. More preferably, the reaction iscarried out for 6 to 24 hours.

On the other hand, after the reaction is completed, a step of purifyingthe product may be included, if necessary.

(Step 3)

The step 3 is a reaction for substituting a carboxyl group of thecompound represented by the Chemical Formula 1-3, wherein the reactionconsists substantially of two reactions.

First, the first reaction is a reaction for preparing a compound of thefollowing Chemical Formula, which is a magnesium salt of the compoundrepresented by the

Chemical Formula 1-4 to be prepared. The second reaction is a reactionfor preparing the magnesium salt of the compound represented by theChemical Formula 1-4 by dissociating the magnesium salt of the compoundrepresented by the Chemical Formula 1-4

The compound represented by the Chemical Formula 1-4 is difficult tocrystallize. Therefore, in the present invention, it is prepared byfirst preparing a magnesium salt thereof and then purifying it throughcrystallization.

First, the first reaction is a reaction of reacting a compoundrepresented by the Chemical Formula 1-3 with (i) methylpotassiummalonate or methylsodium malonate, (ii) carbonyldiimidazole, and (iii)magnesium halide. Preferably, as the magnesium halide, magnesiumchloride or magnesium bromide may be used, and more preferably,magnesium chloride is used.

Preferably, the molar ratio of the compound represented by the ChemicalFormula 1-3 to methylpotassium malonate or methylsodium malonate is 10:1to 1:10, more preferably from 5:1 to 1:5, most preferably 3:1 to 1:3.Preferably, the molar ratio of the compound represented by the ChemicalFormula 1-3 to carbonyldiimidazole is 10:1 to 1:10, more preferably 5:1to 1:5, and most preferably 3:1 to 1:3. Preferably, the molar ratio ofthe compound represented by the Chemical Formula 1-3 to magnesium halideis 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to1:3.

Preferably, the first reaction is carried out in the presence oftriethylamine. Preferably, the molar ratio of the compound representedby the Chemical Formula 1-3 to triethylamine is 10:1 to 1:10, morepreferably 5:1 to 1:5 and most preferably 3:1 to 1:3.

Preferably, as a solvent for the first reaction, acetonitrile ortetrahydrofuran is used, and more preferably, acetonitrile is used.

Preferably, the first reaction is carried out at 50 to 100° C. When thereaction temperature is less than 50° C., there is a problem that theproduction yield is lowered. When the reaction temperature exceeds 100°C., a side reaction occurs, which is not preferable.

Preferably, the first reaction is carried out for 10 minutes to 10hours. When the reaction time is less than 10 minutes, there is aproblem that the reaction does not proceed sufficiently and thus theproduction yield is lowered. When the reaction time exceeds 10 hours, aside reaction occurs, which is not preferable. More preferably, thereaction is carried out for 10 minutes to 5 hours.

After the first reaction is completed, a second reaction is performed inwhich the product of the first reaction is reacted with an acid.

As the acid that can be used, there may be mentioned hydrochloric acid,nitric acid, sulfuric acid, or phosphoric acid, preferably hydrochloricacid.

As the solvent for the second reaction, ethyl acetate, water, methylenechloride, or a mixture thereof may be used. Preferably, ethyl acetateand water are used together.

The second reaction is adjusted to pH 4 to 8 with an acid at 0 to 40° C.When the reaction temperature is less than 0° C. or higher than 40° C.,there is a problem that the production yield is lowered. Preferably itis adjusted to pH 6 to 8. When the pH is 8 or more, the magnesium saltis not completely dissociated, and the production yield is lowered.

On the other hand, after the second reaction is completed, a step ofpurifying the product can be included, if necessary.

(Step 4)

The step 4 is a step of preparing a pyrrole derivative from a compoundrepresented by the Chemical Formula 1-4, which is a step of reacting acompound represented by the Chemical. Formula 1-4 withN,N-dimethylformamide dimethylacetal to prepare a compound representedby the Chemical Formula 1-5.

Preferably, the molar ratio of the compound represented by the ChemicalFormula 1-4 to N,N-dimethylformamide dimethylacetal is 1:1 to 1:10, andmore preferably 1:1 to 1:5.

Preferably, as a solvent for the reaction, toluene or xylene may beused, and more preferably, toluene is used.

Preferably, the reaction is carried out at 20 to 70° C. When thereaction temperature is less than 20° C., there is a problem that theproduction yield is lowered. When the reaction temperature exceeds 70°C., the production yield does not substantially increase.

Preferably, the reaction is carried out for 30 minutes to 12 hours. Whenthe reaction time is less than 30 minutes, there is a problem that thereaction does not proceed sufficiently and thus the production yield islowered. When the reaction time exceeds 12 hours, the production yielddoes not substantially increase.

On the other hand, since the compound represented by the ChemicalFormula 1-5, which is a product of the reaction, is chemically unstable,it is preferable to continuously perform the subsequent reaction of step5 without further purification.

(Step 5)

The step 5 is a reaction of substituting a hydroxy group of the compoundrepresented by the Chemical Formula 1-5 with methoxy, which is a step ofreacting a compound represented by the Chemical Formula 1-5 withdimethyl sulfate to prepare a compound represented by the ChemicalFormula 1-6.

Preferably, the molar ratio of the compound represented by the ChemicalFormula 1-5 to dimethyl sulfate is 10:1 to 1:10, more preferably from5:1 to 1:5, most preferably from 3:1 to 1:3.

Further, the reaction is preferably carried out in the presence of abase. As the base, triethylamine, diisopropylamine,diisopropylethylamine, potassium carbonate, potassium hydrogencarbonate,sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, lithiumhydroxide, potassium hydroxide, sodium methylate, potassium butyrate, orcesium carbonate can be used, and preferably, potassium carbonate isused. In addition, the reaction can be carried out using methyl iodidein the presence of a base. Preferably, the molar ratio of the compoundrepresented by the Chemical Formula 1-5 to the base is 1:1 to 1:5, andmore preferably 1:1 to 1:3.

Preferably, as the solvent for the reaction, an alcohol having 1 to 4carbon atoms or a ketone having 3 to 6 carbon atoms is used. Morepreferably, the solvent for the reaction is methanol, ethanol, propanol,butanol, tert-butanol, acetone, methyl ethyl ketone, or isobutyl ketone.

Preferably, the reaction is carried out at 20. to 60° C. When thereaction temperature is less than 20° C., there is a problem that theproduction yield is lowered. When the reaction temperature exceeds 60°C., a side reaction occurs, which is not preferable.

Preferably, the reaction is carried out for 1 to 24 hours. If thereaction time is less than 1 hour, there is a problem that the reactiondoes not proceed sufficiently and thus the production yield is lowered.When the reaction time exceeds 24 hours, a side reaction occurs, whichis not preferable.

On the other hand, after the reaction is completed, a step of purifyingthe product may be included, if necessary.

(Step 6)

The step 6 is a step of removing a protecting group of the compoundrepresented by the Chemical Formula 1-6, which is a step of reacting thecompound represented by the Chemical Formula 1-6 with an acid to preparea compound represented by the Chemical Formula 1.

As the acid that can be used, there may be mentioned trifluoroaceticacid, hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid,preferably trifluoroacetic acid.

Preferably, the molar ratio of the compound represented by the ChemicalFormula 1-6 to the acid is 1:1 to 1:30, and more preferably 1:5 to 1:20.

Preferably, as a solvent for the reaction, methylene chloride, ethylacetate, methanol, toluene, diethyl ether, tetrahydrofuran, or water maybe used, and preferably, methylene chloride is used.

Preferably, the reaction is carried out at 10 to 40° C. If the reactiontemperature is less than 10° C., there is a problem that the productionyield is lowered. If the reaction temperature exceeds 40° C., a sidereaction occurs, which is not preferable.

Preferably, the reaction is carried out for 1 to 24 hours. When thereaction time is less than 1 hour, there is a problem that the reactiondoes not proceed sufficiently and thus the production yield is lowered.When the reaction time exceeds 24 hours, the production yield does notsubstantially increase.

On the other hand, after the reaction is completed, a step of purifyingthe product may be included, if necessary.

Advantageous Effects

As described above, the preparation method according to the presentinvention has advantages that the production cost can be lowered byusing inexpensive starting materials, a high-temperature reaction is notrequired as a whole, inexpensive and non-explosive reagents are usedinstead of (trimethylsilyl)diazomethane, and further an intermediate of4-methoxypyrrole derivatives can be prepared as a whole at a high yield.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Hereinafter, the present invention will be described in more detail withreference to the following examples. However, the following examples arefor illustrative purposes only and are not intended to limit the scopeof the present invention thereto. On the other hand, in the example andcomparative example, the compounds prepared in each step are used in thenext steps, and each step can produce more products than those describedbelow for the next step.

Example

(Step 1)

35.8 g of ammonium chloride and 26.9 g of sodium cyanide were added to aflask, and 716.0 mL of ammonium hydroxide (25 to 28%) was added and thenstirred for 10 minutes. The mixture was cooled to 0 to 5° C., stirredfor 10 minutes, then heated to room temperature, and stirred for 15minutes. After cooling to 0 to 5° C., 100.0 g of the prepared2,4-difluorobenzaldehyde (Chemical Formula 1-1) and 770.0 mL ofmethanol-containing solution was slowly added to another flask for 15 to20 minutes. The temperature was raised to room temperature, and themixture was stirred for 22 hours to complete the first reaction. Afterconcentration under reduced pressure at 50° C., 983.0 mL of acetic acidand 983.0 mL of conc.HCl were added, and refluxed at 100 to 105° C.(internal temperature) for 5 hours to complete the second reaction. Itwas concentrated under reduced pressure at 75° C., and the solvent wasremoved until a solid was precipitated. After purified water was added,the crystals were precipitated by stirring. The pH was adjusted to 6.5using 5M-NaOH solution at internal temperature of 25° C. or less.Ethanol was added thereto and stirred at 10 to 15° C. for 1 hour. Afterfiltration under reduced pressure, the filtrate was washed with ethanol.The resulting solid was dried under reduced pressure to obtain 78.4 g ofthe compound represented by the Chemical Formula 1-2 (yield: 59.5%).

(Step 2)

100.0 g of the compound represented by the Chemical Formula 1-2 preparedin step 1, 1.5 L of THF and 1.5 L of purified water were added to aflask, and then stirred at room temperature for 10 minutes. The internaltemperature was cooled to 0 to 5° C., and 134.6 g of sodiumhydrogencarbonate and 139.5 g of di-tert-butyl dicarbonate were addedthereto. The mixture was stirred at an internal temperature of 20 to 30°C. for 12 hours to complete the reaction, followed by concentrationunder reduced pressure at 45° C. After ethyl acetate was added, theinternal temperature was cooled to 10° C. or lower. The pH was adjustedto 2.5 using 6N—HCl. The organic layer was separated, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure at45° C. to obtain 151.2 g of the compound represented by the ChemicalFormula 1-3 (yield: 98.5%).

¹H-NMR (500 MHz, CDCl₃): 8.13-8.14; (d, 1H), 7.37-7.42; (m, 1H),6.82-6.89; (m, 2H), 5.46-5.47; (d, 1H), 1.23; (s, 9H)

(Step 3)

100.0 g of the compound represented by the Chemical. Formula 1-3prepared in step 2, 61.9 g of carbonyldiimidazole and 1.0 L ofacetonitrile were added to a flask, and then stirred at room temperaturefor 1 hour. 59.8 g of methyl potassium malonate, 36.4 g of anhydrousmagnesium chloride, 1.0 L of acetonitrile and 38.8 g of triethylaminewere added to another flask and then stirred at 20 to 30° C. for 1 hour.The reactants of the two flasks were mixed and refluxed at an externaltemperature of 80° C. for 1 hour to complete the reaction. After coolingto room temperature, purified water was added. After cooling theinternal temperature to 5 to 10° C., stirring was carried out for 1hour. The obtained solid was filtered under reduced pressure and washedwith purified water. Since the obtained crystal is a magnesium salt, thefollowing salt dissociation process was carried out.

The magnesium salt prepared above, 1.5 L of ethyl acetate and 1.0 L ofpurified water were added to a flask and stirred for 10 minutes. The pHwas adjusted to 7.0 using 6N—HCl. The organic layer was extracted, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure at 45° C. to prepare 97.3 g of the compound represented by theChemical Formula 1-4 (yield: 81.4%).

¹H-NMR (500 MHz, CDCl₃): 7.26-7.30; (m, 1H), 6.85-6.92; (m, 2H), 5.83;(s, 1H), 5.64-5.65; (d, 1H), 3.67; (s, 3H), 3.38-3.52; (dd, 2H), 1.41;(s, 9H)

(Step 4)

100.0 g of the compound represented by the Chemical Formula 1-4 preparedin step 3, and 2.0 L of toluene were added to a flask, and then stirredat room temperature for 10 minutes. 104.1 g of N,N-dimethylformamidedimethylacetal was added and stirred at 40° C. for 4 hours to completethe reaction. After concentration under reduced pressure at 45° C.,ethyl acetate and purified water were added to the concentrated residue,and then stirred for 10 minutes. The pH was adjusted to 7.0 using1N—HCl. The organic layer was extracted, dried over anhydrous magnesiumsulfate, and then concentrated under reduced pressure at 45° C. toproduce 79.2 g of the compound represented by the Chemical Formula 1-5(yield: 77.0%). On the other hand, the compound represented by theChemical Formula 1-5 was unstable (aerial oxidation occurred), thefollowing step 5 was continuously carried out by an in-situ process.

¹H-NMR (500 MHz, CDCl₃): 7.73 (s, 1H), 7.48; (s, 1H), 7.38-7.43; (q,1H), 6.83-6.95; (tt, 2H), 3.90; (s, 3H), 1.39; (s, 9H)

(Step 5)

100.0 g of the compound represented by the Chemical Formula 1-5 preparedin step 4, and 1.5 L of acetone were added to a flask, and then stirredat room temperature for 10 minutes. 78.2 g of potassium carbonate, and42.9 g of dimethyl sulfate were added thereto, and then stirred at 40°C. for 6 hours to complete the reaction. After cooling to roomtemperature, purified water and ethyl acetate were added and stirred for10 minutes. The pH was adjusted to 7.0 using 6N-HCl. The organic layerwas extracted, dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure at 45° C. to obtain 90.6 g of thecompound represented by the Chemical Formula 1-6 (yield: 87.1%). Then,the following step 6 was carried out by an in-situ process withoutfurther purification.

¹H-NMR (500 MHz, CDCl₃): 7.87; (s, 1H), 7.31-7.36; (q, 1H), 6.84-6.95;(tt, 2H), 3.86; (s, 3H), 3.68; (s, 311), 1.38; (s, 91-1)

(Step 6)

100.0 g of the compound represented by the Chemical Formula 1-6 preparedin step 5, and 500.0 mL of methylene chloride were added to a flask, andthen stirred at room temperature for 10 minutes. 310.4 g oftrifluoroacetic acid was added and stirred at room temperature for 6hours to complete the reaction. After cooling to 0 to 5° C., purifiedwater was slowly added at 15° C. or lower. The pH was adjusted to 7.0using a 50.0% NaOH solution at 15° C. or lower. Ethyl acetate was addedand stirred for 10 minutes. The organic layer was extracted and driedover anhydrous magnesium sulfate. The celite washed with ethyl acetatewas placed on a filter, and the organic layer was filtered under reducedpressure and then concentrated under reduced pressure at 45° C. Ethylacetate was added to the concentrated residue and suspended by stirring.n-Hexane was added thereto, the internal temperature was cooled to 0 to5° C., and the mixture was stirred for 1 hour. The obtained solid wasfiltered under reduced pressure. The filtrate was washed with n-hexane,and then dried under reduced pressure to obtain 65.5 g of the compoundrepresented by the Chemical Formula 1 (yield: 90.0%).

¹H-NMR (500 MHz, CDCl₃): 8.78; (s, 1H), 8.12; (m, 1H), 7.30; (d, 1H),6.95; (t, 1H), 6.88; (t, 1H), 3.87; (s, 3H), 3.85; (s, 3H)

Comparative Example

The preparation method was carried out as follows in the same manner asin steps 8-1 to 8-3 of Example 8 of Korean. Patent No. 10-1613245.

(Step 1)

2,4-Difluorophenylglycine (Chemical Formula 2-1, 150.0 g, 801.5 mmol),dimethyl 2-(methoxymethylene)malonate (Chemical Formula 2-2, 126.9 g,728.6 mmol), and sodium acetate (65.8 g, 801.5 mmol) were added tomethanol (800.0 ml), and then refluxed at 60° C. for 4 hours. Thereaction mixture was cooled to room temperature, and concentrated underreduced pressure to remove about 70% of methanol, and then filtered. Theresulting solid was dried under reduced pressure to produce 190.0 g ofthe compound represented by the Chemical Formula 2-3 (yield:

79.2%).

¹H-NMR (500 MHz, CDCl3): 8.02-7.99; (m, 1H), 7.45-7.40; (m, 1H),7.00-6.95; (m, 2H), 5.16; (s, 1H), 3.74; (s, 3H), 3.76; (s, 3H)

(Step 2)

Acetic anhydride (1731.2 ml) and triethylamine (577.1 ml) were added tothe compound represented by the Chemical Formula 2-3 (190.0 g, 577.1mmol) prepared in step 1. The reaction mixture was refluxed at 140° C.for 30 minutes and then cooled to 0° C. To the reaction mixture, icewater (577.1 ml) was added at 0° C., stirred at room temperature for 1hour and then extracted with ethyl acetate. The obtained extract wasdried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The resulting compound was filtered using a silica gelto remove a solid, and then concentrated under reduced pressure toprepare the compound represented by the Chemical Formula 2-4, which wasthen used in the following step 3.

(Step 3)

Tetrahydrofuran (140.0 ml) and water (120.0 ml) were added to theresulting residue, cooled to 0° C., followed by addition of sodiumhydroxide (46.17 g, 1154.2 mmol). The reaction mixture was stirred at 0°C. for 30 minutes, neutralized using IN hydrochloric acid aqueoussolution and then extracted with ethyl acetate. The obtained extract wasdried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (ethyl acetate: n-hexane =1:4 (v/v)) to produce22.0 g of the compound represented by the Chemical Formula 2-5 (yield:15.1%) (including steps 2 and 3).

¹H-NMR (500 MHz, CDCl₃): 8.80; (s, 1H), 8.17-8.12; (m, 2H), 7.13; (d,1H), 6.95; (t, 1H), 6.86-6.83; (m, 1H), 3.88; (s, 3H)

(Step 4)

The compound represented by the Chemical Formula 2-5 (22.0 g, 86.9 mmol)prepared in step 3 was dissolved in tetrahydrofuran (434.5 ml) andmethanol (173.9 ml). (Trimethylsilyl)diazomethane (2.0M diethyl ethersolution, 173.8 ml) was added to the reaction mixture and then stirredat room temperature for 48 hours. Water was added to the reactionmixture, and extracted with ethyl acetate. The obtained extract wasdried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (ethyl acetate: n-hexane=1:4 (v/v)) to produce18.1 g of the compound represented by the Chemical Formula 1 (yield:75.3%).

¹H-NMR (500 MHz, CDCl₃): 8.78; (s, 1H), 8.12; (m, 1H), 7.30; (d, 1H),6.95; (t, 1H), 6.88; (t, 1H), 3.87; (s, 3H), 3.85; (s, 3H)

Comparison of Examples and Comparative Examples

The yields of the preparation methods of the Example and ComparativeExample are shown in Table 1 below.

TABLE 1 Example Comparative Example Total yield 28.8% 9.0% Total yieldfrom 2,4-ditluoroph- 48.4% 9.0% enylglycine to Chemical Formula I

As shown Table 1, it was confirmed that the Example according to thepresent invention could not only reduce the production cost by usinginexpensive aldehyde as a starting material but also improve the yieldby about 5.4 times as compared with the Comparative Example.

In particular, both step 2 of Example according to the present inventionand step 1 of Comparative Example used 2,4-difluorophenylglycine as astarting material. Comparing the methods for preparing the compoundrepresented by the Chemical Formula 1 from the above step, Exampleaccording to the present invention showed a yield of about 50%, whereasComparative Example showed a yield of 9%, thereby confirming that theyield according to the present invention was remarkably improved.

In addition, in Example according to the present invention, therelatively low temperature was applied in the entire steps, whereas instep 2 of Comparative Example, the reaction temperature of about 140° C.was applied. Thus, the preparation method according to the presentinvention has an advantage that a relatively low reaction temperaturecan be applied. Furthermore, step 4 of Comparative Example used(trimethylsilyl)diazomethane which is an explosive reaction material,whereas Example according to the present invention has the advantagethat such a reactant was not used.

What is claimed is:
 1. A method for preparing a compound represented bythe following Chemical Formula 1, comprising the steps of: 1) reacting acompound represented by the following Chemical Formula 1-1 with ammoniumchloride, and sodium cyanide, or potassium cyanide, followed by reactionwith an acid to prepare a compound represented by the following ChemicalFormula 1-2; 2) protecting a compound represented by the followingChemical Formula 1-2 with an amine protecting group (P) to prepare acompound represented by the following Chemical Formula 1-3; 3) reactinga compound represented by the following Chemical Formula 1-3 with (i)methylpotassium malonate, or methylsodium malonate, (ii)carbonyldiimidazole, and (iii) magnesium halide, followed by reactionwith an acid to prepare a compound represented by the following ChemicalFormula 1-4; 4) reacting a compound represented by the followingChemical Formula 1-4 with N,N-dimethylformamide dimethylacetal toprepare a compound represented by the following Chemical Formula 1-5; 5)reacting a compound represented by the following Chemical Formula 1-5with dimethyl sulfate to prepare a compound represented by the followingChemical Formula 1-6; and 6) reacting a compound represented by thefollowing Chemical Formula 1-6 with an acid to prepare a compoundrepresented by the following Chemical Formula 1:


2. The method according to claim 1, wherein in the step 1, the molarratio of the compound represented by the Chemical Formula 1-1 toammonium chloride is 10: 1 to 1:10, and the molar ratio of the compoundrepresented by the Chemical Formula 1-1 to sodium cyanide or potassiumcyanide is 10:1 to 1:10.
 3. The method according to claim 1, wherein inthe step 1, the reaction with the compound represented by the ChemicalFormula 1-1, ammonium chloride, and sodium cyanide or potassium cyanideis carried out at 0 to 40° C., and the reaction with an acid is carriedout at 80 to 120° C.
 4. The method according to claim 1, wherein theacid in the step 1 is acetic acid or hydrochloric acid.
 5. The methodaccording to claim 1, wherein, the amine protecting group (P) in thestep 2 is tert-butoxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc),Tosyl, or Acyl.
 6. The method according to claim 1, wherein the reactionof the step 2 is carried out at 10 to 40° C.
 7. The method according toclaim 1, wherein the magnesium halide in the step 3 is magnesiumchloride or magnesium bromide.
 8. The method according to claim 1,wherein in the step 3, the molar ratio of the compound represented bythe Chemical Formula 1-3 to methylpotassium malonate or methylsodiummalonate is 10:1 to 1:10, the molar ratio of the compound represented bythe Chemical Formula 1-3 to carbonyldiimidazole is 10:1 to 1:10, and themolar ratio of the compound represented by the Chemical Formula 1-3 tothe magnesium halide is 10:1 to 1:10.
 9. The method according to claim1, wherein the acid in the step 3 is hydrochloric acid, nitric acid,sulfuric acid, or phosphoric acid.
 10. The method according to claim 1,wherein the reaction between the compound represented by the Chemical.Formula 1-3 and (i) methylpotassium malonate or methylsodium malonate,(ii) carbonyldiimidazole, and (iii) magnesium halide in the step 3 iscarried out at 50 to 100° C., and the reaction with the acid is carriedout at 0 to 40° C.
 11. The method according to claim 1, wherein themolar ratio of the compound represented by the Chemical Formula 1-4 toN,N-dimethylformamide dimethylacetal in the step 4 is 1:1 to 1:10. 12.The method according to claim 1, wherein the reaction of the step 4 iscarried out at 20 to 70° C.
 13. The method according to claim 1, whereinthe molar ratio of the compound represented by the Chemical Formula 1-5to dimethylsulfate in the step 5 is 10:1 to 1:10.
 14. The methodaccording to claim 1, wherein the reaction of the step 5 is carried outat 20 to 60° C.
 15. The method according to claim 1, wherein the molarratio of the compound represented by the Chemical Formula 1-6 totrifluoroacetic acid in the step 6 is 1:1 to 1:30.
 16. The methodaccording to claim 1, wherein the reaction of the step 6 is carried outat 10 to 40° C.
 17. The method according to claim 1, wherein the acid ofthe step 6 is trifluoroacetic acid, hydrochloric acid, nitric acid,sulfuric acid, or phosphoric acid.